Domestic Avian Diseases
Commercial chicken flocks in most parts of the world are routinely vaccinated to protect them against environmental exposure to pathogens. Some of the more common viruses that cause disease in domestic poultry include Marek's disease virus (MDV), infectious bursal disease virus (IBDV), Newcastle disease virus (NDV), infectious bronchitis virus (IBV), infectious laryngotracheitis virus (ILTV), avian encephalomyelitis (AEV), chick anemia virus (CAV), Fowlpox virus (FPV), avian influenza virus (AIV), reovirus, avian leukosis virus (ALV), reticuloendotheliosis virus (REV), avian adenovirus and hemorrhagic enteritis virus (HEV). These diseases are of economic importance to the poultry industry. Currently, vaccines are available to protect commercial poultry against most of these diseases. (Diseases of Poultry, 10th ed. (Calneck et al., eds.), Iowa State University Press, Ames, Iowa (1997)).
One of the most economically important diseases is Marek's disease (MD). MD is a lymphoproliferative disease that occurs naturally in chickens. The disease is caused by a herpesvirus that is extremely contagious, spreads horizontally, and has been responsible for major economic losses to the poultry industry. Chickens have sensitivity to this virus with no influence of lineage or sex, but it is reported that younger chickens have a higher sensitivity and suffer greater damage from the virus. The symptoms of MD appear widely in the nerves, genital organs, internal organs, eyes and skin of the infected birds causing motor trouble due to paralysis when the nerves have been affected, functional trouble of the internal organs due to tumors, and chronic undernourishment if the internal organs are attacked by the virus. The chickens usually die. MD is one of the leading causes of economic losses in the poultry industry.
Post-hatch Vaccination
In most commercial flocks, newly hatched chicks are given certain vaccines parenterally at hatch. Because exposure to pathogens often occurs at a very young age, they often need to be vaccinated before they are placed in rearing or brooder houses. Such a vaccination scheme requires handling of individual birds and involves the possible risk of accidental self-injection. Another problem with this vaccination method is that the vaccines are not always effective. The young chicks may become exposed to a virulent form of a disease too soon after vaccination, i.e., before they have the opportunity to develop adequate protective immunity.
In ovo Vaccination
It has been shown that certain live viral vaccines can be administered in eggs before the birds hatch. This procedure is called "in ovo vaccination." The in ovo vaccinated birds develop resistance to the target disease. The exact mechanism by which embryonal vaccination results in increased resistance to challenge at hatch is not yet clear. The poultry industry in the U.S. and abroad has responded to the benefits of in ovo vaccination and this procedure is rapidly gaining popularity. Over seven billion birds receive vaccines yearly in the U.S. In 1994, about 30% of the U.S. commercial chicken population was vaccinated against MD by the in ovo procedure. In 1997, the figure has risen to over 75% or about 6.0 billion chickens.
It should be noted, that many vaccines used previously for hatched birds cannot be used for in ovo vaccination because the vaccine agents are pathogenic for the embryo. Late stage embryos are highly susceptible to infection with most vaccine viruses examined. Not all vaccine viruses that are non-pathogenic for newly hatched chicks are also safe for late-stage embryos. For instance, vaccine strains of IBV and NDV that are used routinely as neonatal vaccines in newly hatched chicks are lethal for embryos following in ovo inoculation. These viruses have been modified to render them safe for in ovo use. Currently only the MD vaccine is being administered in ovo.
Use of Inactivated vs. Live Vaccines
Oil-emulsion vaccines prepared with mineral oil are highly efficacious formulations used widely against poultry diseases in various monovalent and polyvalent forms. Mineral oil vaccines, however, cause excessive tissue reactions. Also, the oil persists too long, is practically non-digestible, and is considered carcinogenic. A 42 day holding period is required before slaughter of poultry if a mineral oil vaccine is administered. Animal and vegetable oil vaccines have been developed to replace mineral oil vaccines. However, these have also resulted in tissue reactions.
Live, also called infectious, viral vaccines contain attenuated or naturally non-pathogenic isolates of viruses. The vaccines do not, by themselves, cause disease. The immune response stimulated by live vaccines protects against virulent target viruses present in the environment. Adjuvants such as mineral oil are not needed with live vaccines.
Use of Single vs. Combined Vaccines
Combined or multivalent vaccines offer a number of obvious advantages over monovalent vaccines. One advantage of a multivalent vaccine is that fewer vaccine inoculations are required. A single preparation can be administered in one inoculation and is effective against several diseases. As the range of potential vaccines increases, the combination of vaccines becomes even more mandatory in order to minimize the number of inoculations. The decreased number of inoculations needed when vaccines are combined would likely lead to an increased compliance to the vaccination schedule. This in turn would likely lead to a resulting increase in vaccine coverage, which would ultimately lead to better disease control.
Additional advantages of combined vaccines are the reduced costs of storage, transport and administration since there are fewer vials, ampules, syringes and needles needed. Given the fact that on a worldwide basis more than 90% of the cost of vaccination is caused by such logistic costs, this advantage is certainly not negligible. Also, if several vaccines are combined, vaccine schedules and record keeping is simplified.
Problems with Combined Vaccines
An unexpected problem of combined vaccines is the recently identified negative influence that one vaccine may have on another in a combination vaccine. It has been found that when two existing vaccines are simply mixed, one or both may lose their potency (Andre, F. E., "Development of Combined Vaccines: Manufacturers' Viewpoint," Biologicals 22:317-321 (1994); Hadler, S. C., "Cost benefit of combining antigens," Biologicals 22:415-418 (1994); Goldenthal, K, L., et al., "Overview--Combination Vaccines and Simultaneous Administration. Past, Present, and Future." In: Combined Vaccines and Simultaneous Administration. Current Issues and Perspectives (Eds. Williams, J. C., et al.) The New York Academy of Sciences, New York, pp. 1 XI-XV (1995); Clemens, J., et al., "Interactions between PRP-T Vaccine against Hemophilus influenzae Type b and Conventional Infant Vaccines. Lessons for Future Studies of Simultaneous Immunization and Combined Vaccines," In: Combined Vaccines and Simultaneous Administration. Current Issues and Perspectives (Eds. Williams, J. C., et al.) The New York Academy of Sciences, New York, pp. 255-266 (1995); Insel, R. A., "Potential Alterations in Immunogenicity by Combining or Simultaneously Administering Vaccine Component,". In: Combined Vaccines and Simultaneous Administration. Current Issues and Perspectives (Eds. Williams, J. C., et al.) The New York Academy of Sciences, New York, pp. 35-47 (1995)).
Unfortunately, it cannot always be predicted by the use of currently established potency tests in the laboratory whether individual vaccine components will retain their potency. Developing a multivalent vaccine can be as difficult as developing a new monovalent vaccine. For example, several independent studies reported that when the Hib vaccine is combined with a whole cell pertussis vaccine there is no interference between the two vaccines, but when the Hib vaccine is combined with acellular pertussis vaccines, there is a substantial loss of the Hib immunogenicity. It was shown that when Hib is combined with DTaP, it maintains its immunogenicity if given at separate sites, while the immunogenicity is 5-15 times lower when the vaccines are administered combined at the same site. This unexpected result confirms that combining two existing vaccines is not simple and often gives very unpredictable results that are not detected during the initial studies, but only after extensive clinical testing.
Trials have confirmed that there may not be a direct correlation between antibody titers and protection. This finding indicates that the antibody titers that are measured may not correlate with protective efficacy of vaccines, and therefore that any modification to the vaccine (for instance, the addition of another component to make a combination vaccine), may influence vaccine efficacy without changing the antibody titers.
Another major difficulty in the development of combined vaccines is the unexpectedly large cost of developing these combined vaccines (Andre, F. E., "Development of Combined Vaccines: Manufacuters' Viewpoint," Biologicals 22:317-321 (1994)). While a few years ago it was believed that combining two already existing vaccines would be a simple and inexpensive operation, it has become obvious that the development of a combination requires a long time and a budget which is often similar to that necessary for the development of a new vaccine.
Thus, there is an unmet need for "multivalent" vaccines, i.e. vaccines containing multiple agents, that can be administered to poultry in ovo.